Multiple sclerosis (MS) is a neurological disease of major socioeconomic importance in which a viral etiology is strongly suspected. Because of the historical importance of experimental animal models to understanding human disease, investigation of MS models can be expected to lead to clearer insights into the pathogenesis of this human disease. Of the few available experimental animal models of virus-induced demyelination, Theiler's murine encephalomyelitis virus (TMEV) infection in mice is possibly the most relevant to MS. Clearly, a multidisciplinary approach is needed to answer relevant questions about the molecular pathogenesis of TMEV-induced demyelinating disease. This application represents a request for the renewal of a highly successful collaborative research effort which has been in effect for the past 11 years. This Program Grant is a unique in that it represents the only multidisciplinary approach to the study of the molecular pathogenesis of TMEV infection and of its utility as a model of MS. Funding is requested for the continuation of Projects 1 (Dr. Miller), and 3 (Dr. Lipton), and for the inclusion a new project directed jointly by Drs. Kim and Melvold (Project 2). Project 1 will determine the mechanism(s) by which myelin-specific T cell responses arise during persistent CNS TMEV infection, ascertain their functional contribution to chronic disease pathology, and define the specificity and mechanisms of specific immunoregulation of TMEV-induced demyelinating disease using peripheral tolerance and antagonists of B7/CD28 costimulation. Project 2 will examine the functional contribution of CD8+ cytotoxic T cells in disease pathogenesis and resistance in susceptible and resistant mouse strains. Project 3 will employ molecular and biochemical approaches to identify the host cellular receptor for TMEV and determine its tissue distribution and function. In addition, this project will investigate the mechanisms of persistence of TMEV virions as related to their ability to induce apoptosis in murine cells. Important information relative to the nature, specificity (anti-viral and anti-self), and immunoregulation of immune responses involved in resistance/susceptibility to TMEV-induced demyelination and to the viral and host genetic elements involved in disease resistance/susceptibility, cellular susceptibility to virus infection, and virus persistence should be forthcoming. These studies should add to our understanding of the etiology and immunopathologic mechanisms of tissue injury in MS and other chronic (auto)immune diseases, aid in design of specific treatment strategies, and hopefully lead to innovative approaches which may ultimately link a specific virus(es) with MS.